JP2005522408A - Hexahydroazepino (4,5-g) indole and indoline as 5-HT receptor ligands - Google Patents

Abstract

The present invention includes compounds of formula (I), wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and --- have any of the values defined herein, as well as the compounds A pharmaceutical composition is provided. The present invention also provides methods of treatment and intermediates useful for preparing compounds of formula (I). The compound is useful as a 5-HT ligand.
[Chemical 1]

Description

Detailed Description of the Invention

The present invention provides tricyclic hexahydroazepinoindole and indoline derivatives, and more particularly provides compounds of formula (I) as described below. These compounds are 5-HT ligands and are useful in treating diseases where modulation of 5-HT activity is desired.

BACKGROUND OF THE INVENTION Serotonin has been associated with a number of diseases and disorders that originate from the central nervous system. These include sleep, eating, pain detection, body temperature control, blood pressure control, depression, anxiety, schizophrenia and other illnesses and diseases related to body conditions (RWFuller, Biology of Serotonergic Transmission, Neville V. Osborne, John Wiley and Sons (1982), p221; DJBoullin, Serotonin in Mental Abnormalities 1, John Wiley and Sons (1978), p.316; J. Barchas et al., Serotonin and Behavior, Academic Press, New York, New York (1973)). Serotonin also plays an important role in the peripheral system, such as the gastrointestinal system, where it has been found to mediate various contraction, secretion and electrophysiological effects.

  As a result of the wide distribution of serotonin in the body, much attention has been paid to drugs that affect the serotonergic system. In particular, receptor-specific agonists and antagonists include anxiety, depression, hypertension, migraine, obesity, obsessive compulsive disorder, schizophrenia, autism, neurodegenerative disorders (eg, Alzheimer's disease, Parkinson's disease and Huntington's chorea) , And the treatment of a wide range of disorders, including chemotherapy-induced vomiting (MDGershon et al., The Peripheral Actions of 5-Hydroxytryptamine, 246 (1989); PRSaxena et al., Journal of Cardiovascular Pharmacology, 15: Supplement 7 (1990)).

The main class of serotonin receptors (5-HT _1-7 ) comprises _14-18 distinct receptors that have been officially classified. See Glennon et al., Neuroscience and Behavioral Reviews, 1990, 14, 35; and D. Hoyer et al., Pharmacol. Rev. 1994, 46, 157-203. Recently discovered information on subtype identity, distribution, structure and function suggests that it is possible to identify new subtype specific agents with improved therapeutic profiles (eg, fewer side effects) To do.

For example, the 5-HT ₂ family of receptors has 5-HT _2A , 5-HT _2B , and 5-HT _2C subtypes that have been grouped together based on primary structure, secondary messenger system, and agonist profile It becomes more. All three subtypes are coupled to G-proteins, activate phospholipase as the main conversion mechanism and contain a seven-transmembrane domain structure. There are distinct differences in the distribution of the three 5-HT ₂ subtypes. 5-HT _2B and 5-HT _2A receptors are widely distributed in the periphery, while 5-HT _2C receptors are found only in the central nervous system, which is highly expressed in many areas of the human brain Has been. See G. Baxter et al., Trends in Pharmacol. Sci. 1995, 16, 105-110.

Subtype 5-HT _2A has been associated with effects including vasoconstriction, platelet aggregation and bronchoconstriction, while subtype 5-HT _2C is depression, anxiety, obsessive compulsive disorder, panic disorder, phobia, psychotic syndrome And have been associated with diseases including obesity. Little is known about the pharmacological role of 5-HT _2B receptors. F. Jenck et al., Exp. Opin. Invest. Drugs, 1998, 7, 1587-1599; M. Bos et al., J. Med. Chem., 1997, 40, 2762-2769; JRMartin et al., The Journal of Pharmacology and Experimental Therapeutics, 1998, 286, 913-924; SMBromidge et al., J. Med. Chem., 1998, 41, 1598-1612; GAKennett, Drugs, 1998, 1, 4,456-470; and A. Dekeyne et al., Neuropharmacology, 1999, See 38, 415-423.

  Currently, there is a need for medicaments useful for treating diseases and disorders associated with 5-HT receptors.

SUMMARY OF THE INVENTION The present invention provides novel compounds that exhibit useful biological activity, particularly activity as 5-HT receptor ligands. Thus, the present invention provides compounds of formula (I):

[Wherein the bond represented by --- is absent or present;
R ¹ and R ² are independently hydrogen, halo, C _1-8 alkyl, C _3-8 cycloalkyl, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, C _1-8 alkoxy, C _{1 -8} alkoxycarbonyl, C _1-8 alkanoyloxy, R ⁷ C (═O) —, R ⁸ R ⁷ NC (═O) —, R ⁸ R ⁷ N—, aryl, aryl C _1-8 alkylene-, hetero Aryl, heteroaryl C _1-8 alkylene-, Het, or HetC _1-8 alkylene-; or

R ¹ and R ² together contain one or more carbon atoms, and optionally one or two oxy (—O—), thio (—S—), sulfinyl (—SO 2) in the chain. -), sulfonyl (-S _(O) 2 -), or ^{-NR 10} - including 3-, 4-, 5-, 6-, 7- or 8-membered saturated or partially in chain unsaturated Yes;
R ³ is hydrogen, C _1-8 alkyl, C _3-8 cycloalkyl, aryl, heteroaryl, Het, R ⁷ C (═O) —, R ⁷ OC (═O) —, R ⁷ SO ₂ —, R ^{8 R 7 NC (= O)} -, R 7 C (= S) -, R 7 SC (= O) -, R 8 R 7 NC (= S) -, R 7 SO 2 -, R 8 R 7 NSO _2- , R ⁷ S (═O) —, R ⁸ R ⁷ NS (═O) —, R ^a C _1-8 alkylene-, or R ^a C _1-8 alkylene C (═O) —;

R ^a is aryl, Het, heteroaryl, R ⁷ CO ₂ —, R ⁷ C (═O) —, R ⁷ OC (═O) —, R ⁷ O—, R ⁷ OC _1-8 alkylene O—, R ⁷ S-, R ⁷ C (= S)-, R ⁷ S (= O)-, R ⁷ SC (= O)-, R ⁸ C (= O) N (R ⁷ )-, R ⁸ C (= ^{S) N (R 7) -} , R 8 R 7 N-, R 8 R 7 NC (= O) -, R 8 R 7 NC (= S) -, R 8 R 7 NS (= O) -, R ⁸ R ⁷ NSO ₂ —, R ⁸ S (═O) N (R ⁷ ) —, or R ⁸ SO ₂ N (R ⁷ ) —;
R ⁴ is hydrogen, C _1-8 alkyl, C _3-8 cycloalkyl, aryl, heteroaryl or Het;

R ⁵ and R ⁶ are independently hydrogen, halo, C _1-8 alkyl, C _3-8 cycloalkyl, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, C _1-8 alkoxy, C _{1 -8} alkoxycarbonyl, C _1-8 alkanoyloxy, R ⁷ C (═O) —, R ⁸ R ⁷ NC (═O) —, R ⁸ R ⁷ N—, aryl, aryl C _1-8 alkylene-, hetero Aryl, heteroaryl C _1-8 alkylene-, Het, or HetC _1-8 alkylene-;
R ⁷ and R ⁸ are independently hydrogen, C _1-8 alkyl, C _3-8 cycloalkyl, Het, aryl, heteroaryl, aryl C _1-8 alkylene-, or heteroaryl C _1-8 alkylene- Is;

Where any aryl, heteroaryl or Het of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ is optionally one or more halo, C _{1- 8} alkyl, phenyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, —OR ¹⁰ , —SR ¹⁰ , —SO ₂ R ¹⁰ , —SO ₂ NR ¹⁰ R ¹¹ , —NR ¹⁰ R ¹¹ , —C (═O ^{) NR 10 R 11, -NR 10} C (= O) R 11, -NR 10 C (= O) NR 11 R 12, -CO 2 R 10, -C (= O) R 10, -OC (= O ) R ¹⁰ , optionally substituted with tetrazole, triazole, amidine, guanidine, thioguanidine, or cyanoguanidine;

Here, any ^one of R ¹ , R ² , R ⁵ , R ⁶ , R ⁷ and R ⁸ , C _1-8 alkyl, C _3-8 cycloalkyl, C _1-8 alkoxy, C _1-8 alkanoyl, C _1-8 alkoxycarbonyl or C _1-8 alkanoyloxy is also optionally aryloxy, hydroxy, nitro, halo, cyano, C _1-8 alkoxy, C _1-8 alkanoyl, C _1-8 alkoxycarbonyl, C _{1 -8 ^{alkanoyloxy, R 10 S (O) m}} -, R 11 R 10 NS (O) m -, R 11 R 10 N-, or ^{R 11 R 10 NC (= O} ) - may be substituted by ;

Wherein R ¹⁰ , R ¹¹ and R ¹² are independently hydrogen, C _1-8 alkyl, C _3-8 cycloalkyl, aryl, heteroaryl, aryl C _1-8 alkylene-, or heteroaryl C _{1 -8} alkylene;
Here, any ^one of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ¹⁰ , R ¹¹ and R ¹² , C _1-8 alkyl, C _1-8 Alkylene, C _1-8 alkoxy, C _1-8 alkanoyl, C _1-8 alkoxycarbonyl, C _1-8 alkanoyloxy or C _3-8 cycloalkyl may also be optionally partially unsaturated;
m is 0, 1 or 2]
Or a pharmaceutically acceptable salt thereof.
Special compounds of the invention are represented by formula (II):

^{Wherein, R 1, R 2, R} 3, R 4, R 5 and ^{R 6} are as defined above]
belongs to.
The special compounds of the present invention are represented by the formula (III):

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same as defined above]
belongs to.

In another aspect, the present invention provides:
A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, the composition preferably comprising a therapeutically effective amount of the compound or salt thereof ,
5-HT receptor in a mammal in need thereof (eg, a human), characterized in that a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the mammal A method for treating a disease or disorder in which 5-HT function is desired,

A disease of the central nervous system in a mammal in need thereof, characterized in that a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the mammal in need thereof; A method of treating or preventing a disorder,
A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in medical diagnosis or treatment (eg treatment or prevention of 5-HT related diseases such as anxiety, obesity, depression or stress-related diseases),

Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful for treating or preventing a disease or disorder of the central nervous system in a mammal, and an effective modulating amount Administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, a method of modulating the function of a 5-HT receptor;
I will provide a.
The present invention also provides novel intermediates disclosed herein (formula IV) useful for preparing compounds of formula (I):

[Wherein R ¹ , R ² , R ³ and PG are the same as defined above]
And provide recipe.

DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention are useful for treating or preventing diseases or disorders of the central nervous system. Specific diseases or disorders of the central nervous system in which compounds of formula (I) may have activity include, but are not limited to: obesity, depression, schizophrenia, schizophrenic type disorders, In schizoaffective, delusional disorders, stress-related disorders (eg, general anxiety disorder), panic disorder, phobias, obsessive-compulsive disorder, post-traumatic stress syndrome, immune system decline, urinary system, gastrointestinal or cardiovascular system Stress-induced problems (eg, tension urinary incontinence), neurodegenerative disorders, autism, chemotherapy-induced vomiting, hypertension, migraine, cluster headache, sexual dysfunction in mammals (eg, humans), Sedimentation disorders and withdrawal syndromes, adaptation disorders, age-related learning and mental disorders, anorexia nervosa, dullness of emotion, attention deficit disorder for common medical illnesses, attention deficit disorder, (cognitive decline (eg , Dementia, mental deficiency Behavioral disorders (including agitation in diseases associated with delusions), bipolar abnormalities, anorexia nervosa, chronic fatigue syndrome, abnormal behavior, circulatory temperament disorders, mood disorders, fibromyalgia and Other somatic disorders, generalized anxiety disorders, inhalation disorders, addiction disorders, movement disorders (eg Huntington's disease or tardive dyskinesia), counter-rebellious disorders, peripheral neuropathy, posttraumatic stress disorder, premenstrual discomfort disorder , Neurological disorders (short- and long-term disorders, mental disorders for medical illnesses, mental disorders NOS), mood disorders (severe depressive or bipolar abnormalities with mental characteristics), periodic affective disorders, Includes sleep disorders, specific developmental disorders, severe disturbances, selective serotonin reuptake inhibition (SSRI) “poop out” syndromes or tic disorders (eg Tourette syndrome) It is.
The present invention relates to a compound of formula (I):

[Wherein the bond represented by --- is absent or present;
R ¹ and R ² are independently hydrogen, halo, C _1-8 alkyl, C _3-8 cycloalkyl, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, C _1-8 alkoxy, C _{1 -8} alkoxycarbonyl, C _1-8 alkanoyloxy, R ⁷ C (═O) —, R ⁸ R ⁷ NC (═O) —, R ⁸ R ⁷ N—, aryl, aryl C _1-8 alkylene-, hetero Aryl, heteroaryl C _1-8 alkylene-, Het, or HetC _1-8 alkylene-; or R ¹ and R ^{2 taken} together contain one or more carbon atoms and optionally in the chain one or two oxy (-O-), a thio (-S-), sulfinyl (-SO-), sulfonyl _{(-S (O) 2 -)} , or ^{-NR 10} - including 3, -, 5-, 6-, it is a chain of 7- or 8-membered saturated or partially unsaturated;

R ³ is hydrogen, C _1-8 alkyl, C _3-8 cycloalkyl, aryl, heteroaryl, Het, R ⁷ C (═O) —, R ⁷ OC (═O) —, R ⁷ SO ₂ —, R ^{8 R 7 NC (= O)} -, R 7 C (= S) -, R 7 SC (= O) -, R 8 R 7 NC (= S) -, R 7 SO 2 -, R 8 R 7 NSO _2- , R ⁷ S (═O) —, R ⁸ R ⁷ NS (═O) —, R ^a C _1-8 alkylene-, or R ^a C _1-8 alkylene C (═O) —;
R ^a is aryl, Het, heteroaryl, R ⁷ CO ₂ —, R ⁷ C (═O) —, R ⁷ OC (═O) —, R ⁷ O—, R ⁷ OC _1-8 alkylene O—, R ⁷ S-, R ⁷ C (= S)-, R ⁷ S (= O)-, R ⁷ SC (= O)-, R ⁸ C (= O) N (R ⁷ )-, R ⁸ C (= ^{S) N (R 7) -} , R 8 R 7 N-, R 8 R 7 NC (= O) -, R 8 R 7 NC (= S) -, R 8 R 7 NS (= O) -, R ⁸ R ⁷ NSO ₂ —, R ⁸ S (═O) N (R ⁷ ) —, or R ⁸ SO ₂ N (R ⁷ ) —;

R ⁴ is hydrogen, C _1-8 alkyl, C _3-8 cycloalkyl, aryl, heteroaryl or Het;
R ⁵ and R ⁶ are independently hydrogen, halo, C _1-8 alkyl, C _3-8 cycloalkyl, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, C _1-8 alkoxy, C _{1 -8} alkoxycarbonyl, C _1-8 alkanoyloxy, R ⁷ C (═O) —, R ⁸ R ⁷ NC (═O) —, R ⁸ R ⁷ N—, aryl, aryl C _1-8 alkylene-, hetero Aryl, heteroaryl C _1-8 alkylene-, Het, or HetC _1-8 alkylene-;
R ⁷ and R ⁸ are independently hydrogen, C _1-8 alkyl, C _3-8 cycloalkyl, Het, aryl, heteroaryl, aryl C _1-8 alkylene-, or heteroaryl C _1-8 alkylene- Is;

Wherein any aryl, heteroaryl or Het of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R 7 and R ⁸ is optionally one or more halo, C _1-8 alkyl, phenyl, cyano, nitro, trifluoromethyl, _{^{trifluoromethoxy, -OR 10, -SR 10, -SO}} 2 R 10, -SO 2 NR 10 R 11, -NR 10 R 11, -C (= O) NR ¹⁰ R ¹¹ , —NR ¹⁰ C (═O) R ¹¹ , —NR ¹⁰ C (═O) NR ¹¹ R ¹² , —CO ₂ R ¹⁰ , —C (═O) R ¹⁰ , —OC (═O) Optionally substituted with R ¹⁰ , tetrazole, triazole, amidine, guanidine, thioguanidine, or cyanoguanidine;
Here, any ^one of R ¹ , R ² , R ⁵ , R ⁶ , R ⁷ and R ⁸ , C _1-8 alkyl, C _3-8 cycloalkyl, C _1-8 alkoxy, C _1-8 alkanoyl, C _1-8 alkoxycarbonyl or C _1-8 alkanoyloxy is also optionally aryloxy, hydroxy, nitro, halo, cyano, C _1-8 alkoxy, C _1-8 alkanoyl, C _1-8 alkoxycarbonyl, C _{1 -8 ^{alkanoyloxy, R 10 S (O) m}} -, R 11 R 10 NS (O) m -, R 11 R 10 N-, or ^{R 11 R 10 NC (= O} ) - may be substituted by ;

Wherein R ¹⁰ , R ¹¹ and R ¹² are independently hydrogen, C _1-8 alkyl, C _3-8 cycloalkyl, aryl, heteroaryl, aryl C _1-8 alkylene-, or heteroaryl C _{1 -8} alkylene;
Here, any ^one of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ¹⁰ , R ¹¹ and R ¹² , C _1-8 alkyl, C _1-8 Alkylene, C _1-8 alkoxy, C _1-8 alkanoyl, C _1-8 alkoxycarbonyl, C _1-8 alkanoyloxy or C _3-8 cycloalkyl may optionally be partially unsaturated;
m is 0, 1 or 2]
Or a pharmaceutically acceptable salt thereof.
Special compounds of the invention are represented by the formula (II):

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same as defined above]
belongs to.
Special compounds of the invention are represented by the formula (III):

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same as defined above]
belongs to.
The present invention also provides novel intermediates disclosed herein (formula IV) useful for preparing compounds of formula (I):

[Wherein R ¹ , R ² , R ³ and PG are the same as defined above]
And its manufacturing method.

  Unless otherwise specified, the following definitions are used: halo is fluoro, chloro, bromo or iodo. Alkyl, alkoxy, etc. refer to both straight and branched groups; however, references to individual groups such as “propyl” include only straight chain groups, and branched chain isomers such as “isopropyl” are specifically mentioned. To do. If the alkyl or alkylene can be partially unsaturated, the alkyl chain can contain one or more (eg 1, 2, 3, or 4) double or triple bonds in the chain.

Aryl represents a phenyl group or an ortho-fused bicyclic carbocyclic group having about 9 to 10 ring atoms in which at least one ring is aromatic. Heteroaryl is selected from the group consisting of carbon and N (X), each independently of which non-peroxide oxygen, sulfur and X are absent or are H, O, C _1-8 alkyl, phenyl or benzyl. Of monocyclic aromatic ring groups containing 5 or 6 ring atoms consisting of 1, 2, 3 or 4 heteroatoms, as well as ortho-fused bicyclic heterocycles of about 8 to 10 ring atoms derived therefrom A radical, in particular a benz-derivative or one derived by condensing a propylene, trimethylene or tetramethylene digroup thereto.

  The term “Het” generally refers to a non-aromatic heterocyclic group, which may be saturated or partially unsaturated, independently comprising at least one heteroatom selected from the group consisting of oxygen, nitrogen and sulfur. Represents. Specific “Het” groups include monocyclic, bicyclic or tricyclic groups containing one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur. A “Het” group can also include one or more oxo groups (═O) bonded to ring atoms allowed by the valence. Non-limiting examples of Het groups are 1,3-dioxolanyl, 1,4-dioxanyl, 1,4-dithianyl, 2H-pyranyl, 2-pyrazolinyl, 4H-pyranyl, chromanyl, imidazolidinyl, imidazolinyl, indolinyl, isochromanyl, isoindolinyl, Including morpholinyl, piperazinyl, piperidinyl, piperidyl, pyrazolidinyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuelidinyl, thiomorpholinyl and the like.

  It will be appreciated by those skilled in the art that there can be compounds of the present invention having chiral centers, which are optically active and can be isolated in racemic form. Some compounds can exhibit polymorphism. It is understood that the present invention includes any racemic optically active polymorph, tautomeric or stereoisomeric form of the compounds of the present invention, or mixtures thereof, which possess the useful properties described herein. How to optically (eg by resolution of racemic forms by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis or by chromatographic separation using chiral stationary phases) It is well known how to prepare active forms and how to measure 5-HT activity using standard tests well known in the art.

The carbon content of the various hydrocarbon-containing groups is indicated by a prefix indicating the minimum and maximum number of carbon atoms in the group, ie, the prefix C _ij is generically an integer “i” or an integer A group of carbon atom “j” is shown. Thus, for example, C _1-8 alkyl generically refers to alkyl of 1 to 8 carbon atoms.

  The compounds of the invention are generally named according to the IUPAC or CAS naming system. Abbreviations well known to those skilled in the art can be used. (For example, “Ph” for phenyl, “Me” for methyl, “Et” for ethyl, (h) for time, and “rt” for room temperature). The specific and preferred values listed below for groups, substituents and ranges are for illustrative purposes only. They do not exclude other defined values or other values within defined ranges for groups and substituents.

Specifically, C _1-8 alkyl can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, 3-pentyl, hexyl, or heptyl; C _1-8 alkoxy is methoxy , Ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentoxy, 3-pentoxy, hexyloxy, 1-methylhexyloxy or peptyloxy; C _1-8 alkanoyl is acetyl, propanoyl, butanoyl , Pentanoyl, 4-methylpentanoyl, hexanoyl, or heptanoyl; C _1-8 alkoxycarbonyl is methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxyca Can be sulfonyl, pentoxycarbonyl, hexyloxycarbonyl, or peptyloxycarbonyl, and C _1-8 alkanoyloxy is acetoxy, propanoyloxy, butanoyloxy, isobutanoyloxy, pentanoyloxy, hexanoyloxy Or aryl can be phenyl, indenyl or naphthyl; and heteroaryl can be furyl, imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazolyl, pyrazolyl, pyrrolyl, pyrazinyl, Tetrazolyl, pyridyl (or its N-oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl (or its N-oxide) Or it can be quinolyl (or its N-oxide).

Specific values for R ¹ are hydrogen, halo, C _1-8 alkyl, C _3-8 cycloalkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, C _1-8 alkoxy, aryl or C _{1- 8} alkylene-.
Another specific value for R ¹ is hydrogen.
Another specific value for R ¹ is aryl or substituted aryl.
Another specific value for R ¹ is phenyl.

Specific values for R ² are hydrogen, halo, C _1-8 alkyl, C _3-8 cycloalkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, C _1-8 alkoxy, aryl or aryl C _{1 -8} alkylene.
Another specific value for R ² is hydrogen.
Another specific value for R ² is aryl or substituted aryl.
Another specific value for R ² is phenyl.

Specific values for R ³ are hydrogen, C _1-8 alkyl, C _3-8 cycloalkyl, aryl, heteroaryl, Het, R ⁷ C (═O), R ⁷ SO ₂ —, R ⁸ R ^7. NC (═O) —, R ⁷ SC (═O) —, R ^a C _1-8 alkylene- or R ^a C _1-8 alkylene C (═O) —.
Another specific value for R ³ is hydrogen, C _1-8 alkyl, aryl, R ⁸ R ⁷ NC (═O) C _1-8 alkylene- or R ⁷ OC _1-8 alkylene-.

A specific value for R ⁷ is heteroaryl.
A specific value for R ⁷ is thiazolyl, quinolyl or pyridyl.
Another specific value for R ⁷ is aryl.
More specific values for R ⁷ are phenyl, naphthyl or tetralyl (tetrahydronaphthyl).
Another specific value for R ⁷ is aryl substituted with at least one chlorine, bromine or C _1-8 alkyl.
Another specific value for R ⁷ is aryl substituted with methyl.

A specific value for R ⁴ is hydrogen, C _1-8 alkyl, aryl or substituted aryl.
Another specific value for R ⁴ is hydrogen, methyl or phenyl.

Values for R ⁵ are halo, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, C _1-8 alkoxy, C _1-8 alkoxycarbonyl, C _1-8 alkanoyloxy, aryl or substituted aryl .
A specific value for R ⁵ is hydrogen.
Another specific value for R ⁵ is aryl or substituted aryl.
Another specific value for R ⁵ is phenyl.

The value of R ⁶ is halo, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, C _1-8 alkoxy, C _1-8 alkoxycarbonyl, C _1-8 alkanoyloxy, aryl or substituted aryl.
A specific value for R ⁶ is hydrogen.
Another specific value for R ⁶ is aryl or substituted aryl.
Another specific value for R ⁶ is phenyl.

A specific group of compounds are compounds wherein R ¹ , R ² and R ³ are each hydrogen and R ⁴ is C _1-8 alkyl; and pharmaceutically acceptable salts thereof.
Another specific group of compounds is of the formula (I) wherein R ¹ , R ² , R ⁴ , R ⁵ and R ⁶ are each hydrogen and R ³ is R ^a C _1-8 alkylene- A compound; and pharmaceutically acceptable salts thereof.
Another specific group of compounds is wherein R ¹ , R ² , R ⁵ and R ⁶ are each hydrogen; R ³ is R ^a C _1-8 alkylene-; R ⁴ is C _1-8 A compound of formula (I) which is alkyl-; and a pharmaceutically acceptable salt thereof.

  Specifically, the present invention relates to a mammal in need thereof (for example, a mammal comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof (eg, , Human) anxiety, obesity, depression, schizophrenia, stress-related diseases (eg generally anxiety disorder, panic disorder, autism, obsessive compulsive disorder, post-traumatic-stress syndrome, immune system decline, gastrointestinal or Methods of treating or preventing stress-induced problems or sexual dysfunction associated with the cardiovascular system are provided.

  Specifically, the invention is characterized in that a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to an animal in need of such treatment, such as a human. Also provided are methods of treating or preventing anxiety, obesity, depression or stress-related diseases. Specifically, the present invention relates to anxiety, obesity, depression, schizophrenia, stress-related diseases (eg, generally anxiety disorders), depression disorders, autism, obsessive compulsion in mammals (eg, humans). A compound of formula (I) or a compound thereof for preparing a medicament for treating or preventing disorders, post-traumatic-stress syndrome, immune system decline, stress-induced problems with the gastrointestinal or cardiovascular system, or sexual dysfunction Also provided is the use of a pharmaceutically acceptable salt.

  Specifically, the present invention relates to a compound of formula (I) or a pharmaceutical thereof for preparing a medicament for treating or preventing anxiety, obesity, depression or stress-related disease in a mammal (eg, human) Also provided is the use of acceptable salts.

The present invention also relates to the deprotection of the corresponding compound of formula (I) wherein R ³ or R ⁴ is a suitable nitrogen protecting group, wherein R ³ or R ⁴ is hydrogen Also provided are methods of preparing the compounds.

  The compounds of the present invention can generally be prepared using the synthetic schemes shown in Reaction Schemes 1-4. Starting materials can be prepared by the procedures described in these schemes or by procedures well known to those skilled in organic chemistry. The variables used in the reaction scheme are defined later or are the same as defined in the claims.

  Compounds of formula (I) can be prepared by reactions outlined in Reaction Schemes 1-4. Intermediates used in the synthesis to prepare compounds of formula (I) can be prepared as shown in Reaction Schemes 1 and 2, where the protecting groups (PG) are -COOMe and -Boc, respectively. .

Reaction Scheme 1 shows the synthesis of Intermediates 4 and 6 (PG is COOMe and Boc, respectively). Benzazepine (1) (Pecherer, B. et al., J. Heterocycl. Chem., 9, 609 (1972)) is protected with methyl carbamate and is an organic synthesis such as NH ₄ NO ₃ / H ₂ SO _4. Nitration under standard nitrating conditions well known to those skilled in the art yields a mixture of the two regioisomers 3 and 4, which can be separated by chromatography. Compound 4 is treated with Ba (OH) ₂ to give intermediate 5, where the Boc group can be introduced using standard methods (eg Boc ₂ O / dioxane).

Reaction Scheme 2 shows another method for the preparation of Intermediate 6. Methoxybenzazepine (7) (Pecherer, B. et al., J. Heterocycl. Chem., 9, 609 (1972))) protected with a trifluoroacetyl group and subsequent demethylation with a Lewis acid such as BBr ₃ The hydroxy compound 9 is thus obtained, which is converted into the corresponding triflate 10 under Buchwald / Hartwig conditions. (See Yang, BH et al., J. Organomet. Chem., 576, 125 (1999) and Hartwig, JF, Angew. Chem., Int. Ed. Engt., 37, 2046 (1998)). After the reaction of triflate 10 with benzophenone imine, followed by hydrolysis, aniline 11 can be formed. Aniline 11 is oxidized to give nitro compound 12 and the protecting group is converted to a Boc group to give compound 6.

Compounds of formula (I) can be obtained by constructing an indole ring (see Indoles, Best Synthetic Methods @ Academic Press, 1999, San Diego, CA), Reaction Scheme 3 (where X is H or O). Can be prepared by the reaction outlined in. For example, when X is hydrogen and PG is COOMe, aniline reacts with chloral hydrate and hydroxylamine to form isatin, which is reduced with LiAlH ₄ to form an indole ring. Under the same reaction conditions, the carbamate group is reduced to the methyl group. Alternatively, aniline can be converted to the corresponding hydrazine and then subjected to Fisher indole synthesis conditions to give the indole. Also, aniline reacts with α-haloaldehyde or ketone to form the corresponding α-anilino intermediate, which can lead to indole formation under acidic conditions.

In Reaction Scheme 3, the compound where X is oxygen, the nitro compound can be subjected to Bartoli indole synthesis (see Bartoli, G. et al., Tetrahedron Lett., 30, 2129 (1989)). The conditions used, vinylmagnesium chloride / THF, give indole 14 (R ¹ and R ² are each hydrogen). In compound 15, when R ¹ is hydrogen, electrophilic substitution can lead to the introduction of various electrophiles such as acyl and nitro groups and halogens. When R ¹ or R ² is halogen, 15 compounds can be synthesized with various aryl boronic acids using palladium catalysts such as, for example, Pd (PPh ₃ ) ₄ , Pd ₂ (dba) ₃ , Pd (OAc) _2. It can react to form an arylated indole (see, eg, Miyaura, N. et al., Chem. Rev. 95, 2457 (1995)). In order to introduce R ³ as an aryl or heteroaryl group, palladium dibenzilidine in the presence of various aryl or heteroaryl halides or bases such as sodium tert-butoxide K ₃ PO ₄ containing aryl or heteroaryl triflate The reaction is carried out using a palladium catalyst such as acetone (dba) catalyst (Pd ₂ (dba) ₃ ). (See Old, DW et al., Org. Lett., 2,1403 (2000))).

R ⁴ groups can be introduced by starting with cleavage of the protecting group (15-16) (Protective Groups in Organic Synthesis, 2nd edition @ Greene and Wuts, John Wiley and Sons, Inc, New York (1991 )). Then in a solvent such as acetonitrile or dimethylformamide (DMF) in the presence of a base such as triethylamine or sodium carbonate (see, eg, Glennon et al., Med. Chem. Res, 197 (1996)) or trifluoroacetic acid Secondary amines with alkyl halides or alkyl mesylates under standard reductive alkylation conditions such as treatment with aldehydes in the presence of sodium cyanoborohydride under acidic conditions using an acid such as (TFA) Derivatization yields R ⁴ -substituted products (see, eg, Lane, CF, Sodium Cyanoborohydride-A Highly Selective Reducing Agent for Organic Functional Groups @, Synthesis, 135 (1975)).

  Indole compound 17 can be formed by reducing compound 16 with sodium cyanoborohydride in an acidic medium such as TFA or acetic acid.

Reaction Scheme 4 illustrates the operation of the R ³ group at the indole nitrogen. The indole nitrogen is alkylated with an alkyl halide or alkyl mesylate in a solvent such as acetonitrile or DMF in the presence of a base such as triethylamine, sodium hydride, or sodium carbonate (or cesium) (Glennon et al., Med. Chem. Res., 197 (1996)). For example, ethyl bromoacetate can be used to form compound 19, which is selectively reduced with LiBH ₄ to give alcohol 20. The aryl ether compound 21 is obtained by Mitsunobu reaction with various hydroxy aromatics. For example, deprotection with an acid such as HCl, TFA or β-chlorocatecholborane gives the desired product. Alternatively, compound 22 can be reduced with sodium cyanoborohydride in an acidic medium such as TFA or acetic acid to form indoline compound 23.

  If the compound is sufficiently basic or acidic to form a stable non-toxic acid or base salt, administration of the compound as a salt may be appropriate. Examples of pharmaceutically acceptable salts are pharmacologically acceptable anions such as tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate and α-glycerophosphate. An organic acid addition salt formed with an acid that forms Suitable inorganic salts can also be formed, including hydrochlorides, sulfates, nitrates, bicarbonates and carbonates.

  Pharmaceutically acceptable salts are obtained using standard techniques well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid to obtain a physiologically acceptable anion. Can be obtained. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.

  The compounds of the present invention can be conveniently administered in a pharmaceutical composition containing the compound or salt thereof in combination with a suitable excipient. Such pharmaceutical compositions can be prepared by methods well known in the art and can contain excipients well known in the art. A generally accepted catalog of such methods and ingredients is Remington's Pharmaceutical Sciences (Mark Publ. Co., 15th edition, 1975) by E.W.Martin. The compounds and compositions of the invention can be administered parenterally (eg, by intravenous, intraperitoneal or intramuscular injection), topically, orally or rectally.

  For oral therapeutic administration, the active compound or salt thereof may be combined with one or more excipients and in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc. Can be used. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of compositions and formulations can of course vary, and can conveniently be between about 2 and about 60% by weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.

  Also, tablets, troches, pills, capsules, etc. are as follows: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; disintegration such as corn starch, potato starch, alginic acid, etc. Agents; lubricants such as magnesium stearate; and sweeteners such as sucrose, fructose, lactose or aspartame, or flavoring agents such as peppermint, winter green oil, or cherry flavor. Where the unit dosage form is a capsule, it can contain, in addition to a substance of the type previously described, a liquid carrier such as a vegetable oil or polyethylene glycol. Various other materials can be present as coatings to modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules can be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and / or flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and should be substantially non-toxic in the amounts employed. In addition, the active compound can be integrated into sustained-release formulations and devices.

  The compound or composition can also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

  Pharmaceutical dosage forms suitable for injection or infusion include sterile aqueous solutions or dispersions or powders containing the active ingredient suitable for the immediate preparation of sterile injection or infusion solutions or dispersions, optionally encapsulated in liposomes. Can do. In all cases, the ultimate dosage form should be sterile, liquid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium containing, for example, water, ethanol, polyol (eg glycerol, propylene glycol, liquid polyethylene glycol and the like), vegetable oils, non-toxic glyceryl esters, and suitable mixtures thereof. it can. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersion or by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use of agents that delay absorption, for example, aluminum monostearate and gelatin, in the composition.

  Sterile injectable solutions can be prepared, if necessary, by formulating the required amounts of the active compound together with various other ingredients as described above in a suitable solvent followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred method of preparation is the vacuum drying and lyophilization techniques, whereby the active ingredient previously present in the sterile-filtered solution plus any A powder of further desired ingredients is obtained.

  For topical administration, the compound of the invention or salt thereof can be applied in pure form when it is in liquid form. However, it will generally be desirable to administer it to the skin as a composition or formulation in combination with a dermatologically acceptable carrier which can be solid or liquid.

  Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohol or glycerol or water-alcohol / glycol blends in which the compounds of the invention can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. it can. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given application. The resulting liquid composition can be applied from an absorbent pad and used to impregnate bandages and other dressings or sprayed onto the affected area using a pump type or aerosol sprayer. In addition, thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified cellulose or modified mineral substances can be used with liquid carriers for direct application to the user's skin. Pastes, gels, ointments, soaps, and the like that can be spread over are formed.

  Useful dosages of compounds of formula (I) can be determined by comparing their in vitro and in vivo activities in animal models. Methods for extrapolating effective doses in mice and other animals to humans are known in the art; see, eg, US Pat. No. 4,938,949.

  The compound is conveniently administered in a unit dosage containing, for example, from about 0.05 mg to about 500 mg per unit dosage form, conveniently from about 0.1 mg to about 250 mg, most conveniently from about 1 mg to about 150 mg of the active ingredient. Administered in the form. The desired dose can conveniently be given in a single dose, or administered as divided doses administered at appropriate intervals, eg, 2, 3, 4 or more sub-doses per day be able to. The sub-dose itself can be further divided into, for example, a number of distinctly spaced administrations.

The composition is conveniently administered orally at a dosage level of about 0.01 to about 150 mg / kg, preferably about 0.1 to about 50 mg / kg, more preferably about 0.1 to about 10 mg / kg mammalian body weight. Sublingual, transdermal or parenteral administration.
For parenteral administration, the compound is provided in an aqueous solution at a concentration of about 0.1 to about 10%, more preferably about 0.1 to about 7%. The solution can contain other ingredients such as emulsifiers, antioxidants or buffers.

  The exact method for administration of the compounds and compositions disclosed herein will necessarily depend on the needs of the individual subject to be treated, the type of treatment and, of course, the judgment of the attendant Will.

  Also, the ability of the compounds of the invention to act as agonists or antagonists of 5-HT receptors can be measured using in vitro and in vivo assays known in the art. The present invention provides compounds of formula (I) that act as either agonists or antagonists of one or more 5-HT receptor subtypes. The compounds of the invention are typically 5-HT ligands that displace> 50% of radiolabeled test ligands from one or more 5-HT receptor subtypes at a concentration of 1 μM. The techniques used to test such replacements are well known and will be readily available to those skilled in the art. See, for example, L.W. Fitzgerald et al., Mol. Pharmacol, 2000, 57, 1, 75-81; and D.B. Wainscott et al., J. Pharmacol Exp The, 1996, 276, 2, 720-727.

Description of preferred embodiments Preparation Example 1: Preparation of tert-butyl 6-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate

Step a. Methyl 1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate In a flame-dried 2 L three-necked flask, 2,3,4,5-tetrahydro-1H-3-benzazepine (95.0 g, 0.645 mol), sodium bicarbonate (108.4 g, 1.29 mol), THF (600 mL) and water (600 mL). The flask was cooled to 0 ° C. and methyl chloroformate (62.3 mL, 0.81 mol) was added dropwise over 30 minutes. The bath was removed and the mixture was stirred at room temperature for 16 hours. EtOAc was added, the mixture was separated and the aqueous layer was further extracted with EtOAc. The combined organic layers are concentrated to give 133 g (100%) of the title product as a clear oil that crystallizes at room temperature: ¹ H NMR (300 MHz, CDC1 ₃ ) δ 7.15-7. 13 (m, 4 H), 3.76 (s, 3 H), 3.71-3.53 (m, 4 H), 2.99-2.82 (m, 4 H); MS (ESI +) m / z 206 (M + H) ⁺ .

Step b. (Each) methyl 7-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate and 6-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine-3 -Methyl carboxylate A 2 L three-necked flask was charged with methyl 1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (132.4 g, 0.645 mol) and sulfuric acid (400 mL). In a separate flask, at −5 ° C., ammonium nitrate (54.2 g, 0.677 mol) was added to a solution of sulfuric acid (400 mL) cooled in an ice-brine bath and stirred until homogeneous. At −5 ° C., an ammonium nitrate / sulfuric acid solution was added over 1 hour to a solution of 1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate in sulfuric acid. After 1.5 hours, the solution was poured onto ice (2 L). The aqueous mixture was extracted first with EtOAc and then with CH ₂ Cl ₂ . The organic layer was concentrated and dried over magnesium sulfate to give 59.5 g of orange oil (37%). The oil was subjected to preparative HPLC, the isomers were separated and purified to give the title compound methyl 6-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate. Pure samples of (1%) and methyl 7-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (20%) were obtained. For methyl 7-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate: IR (diffuse reflection) 1693, 1517, 1471, 1440, 1415, 1345, 1318, 1310, 1270, 1243, 1199, 1108, 953, 895, 751cm -1; as elemental analysis _{C l2 H l4 N 2 O 4} :. calculated C, 57.59; H, 5.64; N, 11.19 Found: C, 57.56; H , 5.79; N, 11.19. For methyl 6-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate: ¹ H NMR (300 MHz, CDC1 ₃ ) δ 7.54 (dd, J = 1, 8 Hz, 1 H), 7.35-7.33 (m, 1 H), 7.24 (t, J = 8 Hz, 1 H), 3.71 (s, 3 H), 3.70-3.61 (m, 4 H ), 3.08-2.96 (m, 4 H); MS (FAB) m / z 251 (MH +); HRMS (FAB) C _l2 H _l4 N ₂ O ₄ + H Calculated value 251.1032, Found value 251.1040; Elemental analysis C as _{l2 H l4 N 2 O 4:} . calculated C, 57.59; H, 5.64; N, 11.19 Found: C, 57.41; H, 5.69 ; N, 11.22.

Step c. Maleate of 6-nitro-2,3,4,5-tetrahydro-1H-3-benzazepine 6-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (1. 05 g, 4.2 mmol) was dissolved in methanol (3.0 mL) and barium hydroxide octahydrate (6.31 g, 0.020 mol) and water (6.0 mL) were added and the mixture was added to 100 mL. Heat at 16 ° C. for 16 hours. The mixture was filtered and the filtrate was concentrated and partitioned between EtOAc and water. The organic layer was concentrated to obtain 0.80 g of orange or brown oil. By column chromatography (elution with 1-5% CHCl ₃ / MeOH with methanolic ammonia), 0.62 mg (78%) of 6-nitro-2,3,4,5-tetrahydro-1H-3- Benzazepine was obtained as an orange oil. Part of it was converted to maleate to give a white solid. Melting point 193-195 ° C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.88 (br, 2 H), 7.74 (dd, J = l, 8 Hz, 1 H), 7.57 (dd, J = 1, 7 Hz, 1 H), 7.44 (t, J = 8 Hz, 1 H), 6.03 (s, 2 H), 3.29-3.20 (m, 6 H), 3.16-3.13 (m, 2 H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 167.1, 159.2, 150.4, 142.8, 136.0, 133.4, 132.6, 127.8, 122.2, 44.4, 43.9, 31.6, 25.6; IR (diffuse reflection) 1630, 1570, 1527, 1498 , 1491, 1458, 1393, 1349, 1327, 1005, 983, 866, 746, 731, 714cm ^-1 ; MS (EI) m / z 192 (M +); HRMS (FAB) C ₁₀ H ₁₂ N ₂ O ₂ + As H Calculated 193.0977, Observed 193.0980; Elemental Analysis C ₁₀ H ₁₂ N ₂ O ₂・ C ₄ H ₄ O ₄ As: Calculated C, 54.54; H, 5.23; N, 9.09. Observed: C, 54.50; H, 5.27; N, 9.08.

Step d. Preparation of 6-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-tert-butyl carboxylate 6-nitro-2,3,4,5-tetrahydro-1H-3-benzazepine (0 .51 g, 2.65 mmol) was dissolved in dioxane (4.0 mL) and di-tert-butyl dicarbonate (0.65 g, 3.0 mmol) was added. Once the initial exothermic reaction was complete, the solution was heated to 100 ° C. for 1 hour. The solution was then concentrated and partitioned between EtOAc and water. The organic layer was concentrated to obtain 0.85 g of amber oil. Column chromatography (elution with 10-20% EtOAc / heptane) gave 0.75 g (97%) of the title compound as a clear oil. Crystallization from EtOAc / hexanes gave 0.68 g of white crystals. Melting point 73-76 ° C; ¹ H NMR (400 MHz, CDC1 ₃ ) δ 7.54 (dd, J = 1, 8 Hz, 1 H), 7.34 (d, J = 7 Hz, 1 H), 7.24 (t, J = 8 Hz, 1 H), 3.66-3.60 (m, 4 H), 3.02-2.99 (m, 4 H), 1.42 (s, 9 H); IR (diffuse reflection) 1676, 1531, 1468, 1454, 1427, 1366, 1314, 1301, 1267, 1241, 1170, 1108, 948, 807, 739cm ^-1 ; MS (EI) m / z 292 (M +); HRMS (FAB) C _l5 H ₂₀ N ₂ O ₄ + H As calculated 293.1501, measured 293.1498; elemental analysis C1 ₅ H ₂₀ N ₂ O ₄ as: calculated C, 61.63; H, 6.89; N, 9.58. Found: C, 61.66; H, 6.95; N, 9.55.

  Preparative Example 2: Another preparation of tertbutyl 6-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate

Step a. 6-methoxy-3- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H-3-benzazepine 6-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (19.11 g , 0.119 mol), CH ₂ Cl ₂ (100 mL) and triethylamine (16.7 mL, 0.119 mol) were combined and the solution was cooled to 0 ° C. Trifluoroacetic anhydride (16.2 mL, 0.119 mol) was added slowly via a dropping funnel. The solution was then stirred at room temperature for 72 hours. More CH ₂ Cl ₂ was added and the solution was partitioned between CH ₂ Cl ₂ and water. After extraction with NaHCO ₃ and washing with H ₂ O, the organic layer was concentrated to give 27.6 g of a brown liquid. Column chromatography (elution with 10-20% EtOAc / heptane) afforded 20.5 g (70%) of the title compound as a brown oil. Crystallization from EtOAc / hexanes gave 12.9 g of off-white crystals. Melting point 75-78 ° C; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.16-7.12 (m, 1 H), 6.81 (m, 2 H), 3.81 (s, 3 H), 3.81-3.71 (m, 2 H), 3.70-3.64 (m, 2 H), 3.12-3.07 (m, 2 H), 2.99-2.95 (m, 2 H); IR (diffuse reflection) 1681, 1468, 1269, 1209, 1189, 1176 , 1166, 1151, 1136, 1088, 1004, 950, 780, 754, 739cm ^-1 .MS (EI) m / z 273 (M +); Elemental analysis C _l3 H ₁₄ F ₃ NO ₂ as: Calculated value C, 57.14 ; H, 5.16; N, 5.13; F, 20.86. Found: C, 57.23; H, 5.15; N, 5.17.

Step b. 3- (Trifluoroacetyl) -2,3,4,5-tetrahydro-1H-3-benzazepine-6-ol 6-methoxy-3- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H -3-Benzazepine (11.5 g, 42.0 mmol) was dissolved in CH ₂ Cl ₂ (200 mL) and cooled to 0 ° C. under nitrogen. Boron tribromide (10.0 mL, 0.105 mol) was added via syringe and the solution was stirred at room temperature for 16 hours. Saturated ammonium chloride was added slowly over 2 hours with stirring. More CH ₂ Cl ₂ was added and the solution was partitioned between CH ₂ Cl ₂ and water. The resulting mixture was concentrated and partitioned again between ethyl acetate and H ₂ O. The organic layer was concentrated to give a white solid. Recrystallization from EtOAc / hexanes afforded 9.95 g (91%) of the title compound as a white crystalline solid. Melting point 183-186 ° C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.93 (dt, J = 2, 8 Hz, 1 H), 6.71 (dd, J = 4, 8 Hz, 1 H), 6.61 (t, J = 6 Hz, 1 H), 3.68-3.60 (m, 4 H), 3.00-2.88 (m, 4 H); IR (diffuse reflection) 3311, 1671, 1466, 1375, 1337, 1313, 1277, 1217, 1199, 1175, 1160, 1147, 949, 785, 739 cm ^-1 ; MS (EI) m / z 259 (M +); Elemental analysis as C ₁₂ H ₁₂ F ₃ NO ₂ : Calculated C, 55.60; H, 4.67; N, 5.40; F, 21.99. Found: C, 55.24; H, 4.75; N, 5.36.

Step c. 3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-1H-3-benzazepin-6-yltrifluoromethanesulfonate In a 500 mL three-necked flask under nitrogen, 3- ( trifluoroacetyl) -2,3,4,5-tetrahydro-1H-3- benzazepine-6-ol (3.97 g, 15.3 _mmol) CH ₂ Cl _{2 (150mL)} and triethylamine (6.4 mL, 45. 9 mmol). The solution was cooled to 0 ° C. Trifluoromethanesulfonic anhydride (7.7 mL, 45.9 mmol) was added slowly via syringe over 15 minutes and the solution was stirred at room temperature for 16 hours. Saturated ammonium chloride was added slowly over 2 hours with stirring. More CH ₂ Cl ₂ was added and the solution was partitioned between CH ₂ Cl ₂ and water. After extraction with NaHCO ₃ and washing with H ₂ O, the organic layer was concentrated to give 8.0 g of brown oil. Column chromatography (elution with 5-20% EtOAc / heptane) afforded 5.69 g (95%) of the title compound as an oil. An analytical sample was crystallized from EtOAc hexanes to give white crystals. Melting point 59-61 ° C; ¹ H NMR (400 MHz, CDC1 ₃ ) δ 7.30-7.17 (m, 3 H), 3.82-3.79 (m, 2 H), 3.74-3.71 (m, 2 H), 3.11-3.04 (m, 4 H); IR (diffuse reflection) 1686, 1466, 1397, 1251, 1208, 1172, 1167, 1150, 1137, 947, 891, 882, 852, 814, 806cm ^-1 ; MS (EI) m / z 391 (M +); Elemental analysis as C ₁₃ H ₁₁ F ₆ NO ₄ S: Calculated C, 39.90; H, 2.83; N, 3.58; S, 8.19; F, 29.13.Observed: C, 39.89; H , 2.85; N, 3.70.

Step d. 3- (Trifluoroacetyl) -2,3,4,5-tetrahydro-1H-3-benzazepine-6-amine Palladium acetate (0.60 g, 2.7 mmol) in a 500 mL three-necked flask that was flame-dried under nitrogen. ), (S) -BINAP (2.5 g, 4.0 mmol), THF (80 mL), 3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-1H-3 -Benzazepin-6-yl trifluoromethanesulfonate (11.7 g, 30.0 mmol), benzophenone imine (6.5 mL, 38.9 mmol) and cesium carbonate (9.8 g, 29.9 mmol) were charged. The mixture was heated at 65 ° C. for 16 hours. The mixture was cooled, ether was added and the mixture was filtered through celite. The filtrate was concentrated to give 20.8 g of brown oil, combined with a previous lot of the imine intermediate (3.4 g) and subjected to column chromatography (elution with 5-20% EtOAc / heptane). . The combined fractions containing the desired compound were collected and concentrated to give 11.8 g of a yellow solid that was contaminated with benzophenone. The solid was crystallized to give 7.82 g of imine intermediate as yellow crystals. The mother liquor was subjected to a second column chromatography (elution with 5-20% EtOAc / heptane) to give an additional 3.37 g imine intermediate.

This intermediate (10.27 g, 24.3 mmol) was dissolved in THF (75 mL), HCl 225 mL, 2N) was added and the solution was stirred at room temperature for 1 h. The solution was concentrated and washed with HCl (approximately 200 mL of 1N) and hexane: EtOAc (2: 1, 400 mL) to remove residual benzophenone impurities. The aqueous layer was then separated and sodium bicarbonate was added slowly with stirring until the pH of the mixture was 7-8. Extraction with CH ₂ Cl ₂ (2 × 250 mL) and concentration of the organic layer afforded 6.2 g (98%) of the title compound as a clear oil. An analytical sample was crystallized from EtOAc / hexanes to give white crystals. Melting point 85-88 ° C; ¹ H NMR (400 MHz, CDC1 ₃ ) δ 7.00-6.95 (m, 1 H), 6.65-6.58 (m, 2 H), 3.82-3.70 (m, 4 H), 3.61 (br s, 2 H), 2.98-2.95 (m, 2 H), 2.88-2.84 (m, 2 H); IR (diffuse reflection) 3383, 3253, 1687, 1467, 1382, 1300, 1224, 1212, 1202, 1166, 1126, 778, 756, 730, 662cm ^-1 ; MS (EI) m / z 258 (M +); elemental analysis as C ₁₂ H ₁₃ F ₃ N ₂ O: calculated C, 55.81; H, 5.07 , 10.85; F, 22.07. Found: C, 55.87; H, 5.12; N, 10.84.

Step e. 6-Nitro-3- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H-3-benzazepine Sodium perborate tetrahydrate (5) was added to a flame-dried 100 mL three-necked flask under nitrogen. .75 g, 37.4 mmol) and acetic acid (20 mL) and charged with 3- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H-3-benzazepine-6-amine (1 .93 g, 7.5 mmol) solution was added slowly over 30 minutes. The mixture was stirred at 55 ° C. for 1 hour. The mixture was filtered and partitioned between CH ₂ Cl ₂ and water. The organic layer was washed with water and concentrated to give 2.24 g of amber oil. Column chromatography (elution with 10-25% EtOAc / heptane) gave 1.52 g (70%) of the title compound as a yellow oil. An analytical sample was crystallized from EtOAc / hexanes to give off-white crystals. Melting point 64-67 ° C; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.63 (d, J = 8 Hz, 1 H), 7.41-7.29 (m, 2 H), 3.89-3.74 (m, 4 H), 3.15-3. 10 (m, 4 H); IR (diffuse reflection) 1687, 1523, 1466, 1451, 1376, 1368, 1295, 1197, 1186, 1179, 1168, 1147, 950, 818, 752 cm ^-1 ; MS (EI) m / z 288 (M +); elemental analysis as C ₁₂ H ₁₁ F ₃ N ₂ O ₃ : calculated C, 50.01; H, 3.85; N, 9.72; F, 19.77. Found: C, 49.95 ; H, 3.88; N, 9.68.

Step f. 6-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-tert-butyl carboxylate In a round bottom flask, 6-nitro-3- (trifluoroacetyl) -2,3,4, 5-Tetrahydro-1H-3-benzazepine (5.17 g, 17.9 mmol) was dissolved in dioxane (50 mL) and sodium hydroxide (4N, 13.4 mL, 53.8 mmol) was added. The solution was stirred at room temperature for 2 hours. Di-tert-butyl dicarbonate (7.83 g, 35.9 mmol) was added and the solution was stirred for an additional 16 hours. The solution was concentrated and partitioned between EtOAc and water and the organic layer was concentrated to give 7.1 g of oil. Column chromatography (elution with 10-30% EtOAc / heptane) gave 5.11 g (98%) of the title compound as an amber oil. The physical properties of the compound obtained were identical to those of the compound obtained from Preparation Example 1.

Preparation Example 3:
Preparation of tert-butyl 1- (2-hydroxyethyl) -6,7,9,10-tetrahydroazepino [4,5-g] indole-8 (1H) -carboxylate

Step a. 6,7,9,10-tetrahydroazepino [4,5-g] indole-8 (1H) -tert-butylcarboxylate 6-nitro-1,2, in a 500 mL three-necked flask flame-dried under nitrogen Charged tert-butyl 4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (5.49 g, 18.8 mmol) and anhydrous THF (150 mL) and cooled the solution to −40 ° C. Vinylmagnesium bromide (100 mL, 94.0 mmol) was added via cannula and the solution was stirred at −20 to −40 ° C. for 1.5 hours. Saturated ammonium chloride was added and the mixture was warmed to room temperature. The mixture was then partitioned between EtOAc and water. The organic layer was washed with water, and the organic layer was concentrated to obtain 6.72 g of a brown solid. The mixture was then triturated with CH 2 Cl 2 and filtered to give 2.39 g (44%) of the title compound as a beige solid. The remaining filtrate was subjected to column chromatography (eluting with 15-25% EtOAc / heptane) to give an additional 0.26 g (5%) of the title compound as an off-white solid. An analytical sample was obtained by triturating with CH ₂ Cl ₂ and ether to give white crystals. Melting point 226-229 ° C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.95 (br, 1 H), 7.27-7.25 (m, 2 H), 6.79 (d, J = 8 Hz, 1 H), 6.38-6.36 (m, 1 H), 3.55-3.47 (m, 4 H), 3.17-3.08 (m, 2 H), 2.98-2.89 (m, 2 H), 1.40 (s, 9 H); IR ( (Diffuse reflection) 3289, 2965, 1664, 1475, 1440, 1419, 1365, 1356, 1303, 1226, 1162, 1121, 802, 738, 724cm ^-1 ; MS (EI) m / z 286 (M +); HRMS ( FAB) Calculated as C ₁₇ H ₂₂ N ₂ O ₂ + H 287.1759, found 287.1758; Elemental analysis As C ₁₇ H ₂₂ N ₂ O ₂ : Calculated C, 71.30; H, 7.74; N, 9.78. C, 71.14; H, 7.71; N, 9.63.

Step b. 1- (2-Ethoxy-2-oxoethyl) -6,7,9,10-tetrahydroazepino [4,5-g] indole-8 (1H) -tert-butylcarboxylate 250 mL of flame-dried under nitrogen A three-necked flask was charged with sodium hydride (0.56 g, 13.9 mmol) and anhydrous DMF (20 mL) and cooled to 0 ° C. Suspension of tert-butyl 6,7,9,10-tetrahydroazepino [4,5-g] indole-8 (1H) -carboxylate (2.66 g, 9.3 mmol) in anhydrous DMF (30 mL) The solution was added and the mixture was stirred at 0 ° C. for 1 hour and then at room temperature for 30 minutes. Ethyl bromoacetate (2.06 mL, 18.6 mmol) was added and the mixture was stirred at room temperature for 16 hours. The mixture was partitioned between EtOAc and water, the organic layer was washed with water and the organic layer was concentrated to give 4.32 g of brown oil. Unreacted starting material was removed by dissolution of the oil in CH ₂ Cl ₂ and filtration of the resulting precipitate. Column chromatography of the filtrate (elution with 20-50% Et ₂ O / heptane) gave 2.11 g (61%) of the title compound as a white solid. Melting point 111-115 ° C; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.37 (d, J = 8 Hz, 1 H), 6.93-6.90 (m, 2 H), 6.48 (d, J = 3 Hz, 1 H), 4.98 (s, 2 H), 4.24 (q, J = 7 Hz, 2 H), 3.60-3.57 (m, 4 H), 3.17-3.13 (m, 2 H), 3.04-3.00 (m, 2 H), 1.44 (s, 9 H), 1.29 (t, J = 7 Hz, 3 H); MS (EI) m / z 372 (M +); HRMS (FAB) C ₂₀ H ₂₆ N ₂ O ₄ + As H Calculated 359.1971, Found 359.1972; Elemental Analysis As C ₂₁ H ₂₈ N ₂ O ₄ : Calculated C, 67.72; H, 7.58; N, 7.52. Found: C, 68.06; H, 7.70; N, 7 . 73.

Step c. 1- (2-hydroxyethyl) -6,7,9,10-tetrahydroazepino [4,5-g] indole-8 (1H) -tert-butyl carboxylate Flame-dried 100 mL three-necked flask under nitrogen Was charged with sodium borohydride (0.39 g, 17.0 mmol) and anhydrous THF (10 mL) and cooled to −10 ° C. Tert-Butyl 1- (2-ethoxy-2-oxoethyl) -6,7,9,10-tetrahydroazepino [4,5-g] indole-8 (1H) -carboxylate in anhydrous THF (20 mL) ( 2.11 g, 5.66 mmol) was added and the mixture was allowed to warm to room temperature and stirred for 2 hours. An additional equivalent of lithium borohydride (0.13 mL, 5.66 mmol) was added and the mixture was stirred at room temperature for 16 hours. Water was added slowly and the mixture was partitioned between EtOAc and water. The combined organic layers were concentrated to give 2.09 g of oil. Column chromatography (elution with 10-30% Et2O / hexane) gave 1.70 g (91%) of the title compound as a clear oil. An analytical sample was crystallized from EtOAc / hexanes to give a white solid. Melting point 109-111 ° C; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.38 (d, J = 8 Hz, 1 H), 7.03 (d, J = 3 Hz, 1 H), 6.90 (d, J = 8 Hz, 1 H), 6.45 (d, J = 3 Hz, 1 H), 4.45 (t, J = 5 Hz, 2 H), 3.99-3.88 (m, 2 H), 3.72-3.54 (m, 4 H ), 3.39-3.25 (m, 2 H), 3.10-2.99 (m, 2 H), 1.38 (s, 9 H); IR (diffuse reflection) 3470, 2976, 1666, 1457, 1428, 1369, 1350, 1312, 1267, 1251, 1192, 1178, 1081, 816, 720cm ^-1 ; MS (EI) m / z 330 (M +); Elemental analysis as C ₁₉ H ₂₆ N ₂ O ₃ : Calculated value C, 69.06; H, 7.93; N, 8.48. Found: C, 68.92; H, 7.94; N, 8.43.

Example 1
8-Methyl-1,6,7,8,9,10-hexahydroazepino [4,5-g] indole

A 50 mL two-necked flask, flame dried under nitrogen, was charged with LiAlH ₄ (0.10 g, weight equivalent) and THF (3.0 mL) and cooled to 0 ° C. Then a solution of methyl 6,7,9,10-tetrahydroazepino [4,5-g] indole-8 (1H) -carboxylate (0.105 g, 0.43 mmol) in THF (2.0 mL). Was added and the mixture was stirred at room temperature for 16 hours. Water (0.1 mL) was added slowly followed by 15% NaOH (0.1 mL) followed by water (0.3 mL). The mixture was stirred for 30 minutes, celite was added, the mixture was filtered through celite, and the filtrate was concentrated to give 84 mg (98%) of crude product. Crystallization from EtOAc / hexanes afforded 27 mg of the title product as a beige solid. Melting point 150-153 ° C; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.09 (br, 1 H), 7.39 (d, J = 8 Hz, 1 H), 7.17 (t, J = 3 Hz, 1 H) , 6.91 (d, J = 8 Hz, 1 H), 6.53 (dd, J = 2, 3 Hz, 1 H), 3.10-3.05 (m, 4 H), 2.67-2.62 (m, 4 H), 2.40 (s, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 135.5, 135.0, 126.5, 123.8, 123.8, 123.6, 121.9, 118.0, 103.1, 57.7, 56.8, 47.6, 36.2, 29.3; HRMS (FAB) Calculated as C ₁₃ H ₁₆ N ₂ + H 201.1392, measured 201.1390.

  The intermediate 6,7,9,10-tetrahydroazepino [4,5-g] indole-8 (1H) -carboxylate methyl was prepared as follows.

1 (a). 6,7,9,10-Tetrahydroazepino [4,5-g] indole-8 (1H) -carboxylate 6-nitro-1,2,4 in a 100 mL two-necked flask, flame-dried under nitrogen. 5-Tetrahydro-3H-3-benzazepine-3-carboxylate (0.85 g, 3.4 mmol) and THF (20 mL) were charged and cooled to −40 ° C. Vinylmagnesium bromide (11.2 mL, 11.2 mmol) was added and the solution was stirred for 30 minutes and warmed to −20 ° C. Ammonium chloride was added and the mixture was partitioned between EtOAc and water. The organic layer was concentrated to give 0.88 g of brown oil. Column chromatography (elution with 10-30% EtOAc / heptane) afforded 0.28 g (34%) of the title compound as a solid. Crystallization from EtOAc / hexanes gave 0.192 g of a white solid. Melting point 169-171 ° C; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41 (d, J = 8 Hz, 1 H), 7.19-7.17 (m, 1 H), 6.90 (d, J = 8 Hz, 1 H), 6.53-6.52 (m, 1 H), 3.76 (s, 3 H), 3.72-3.63 (m, 4 H), 3.19-3.10 (m, 1 H), 3.00-3.10 (m, 3 H) ¹³ C NMR (100 MHz, CDCl ₃ ) δ 156.6, 135.5, 134.1, 133.6, 126.6, 124.3, 122.7, 118.3, 102.9, 52.7, 47.4, 46.0, 37.3, 30.4; IR (diffuse reflection) 3313, 1673, 1476, 1446, 1414, 1275, 1260, 1237, 1217, 1115, 947, 805, 764, 745, 731cm ^-1 ; MS (EI) m / z 244 (M +); Elemental analysis C ₁₄ H ₁₆ N ₂ O ₂ As: Calculated C, 68.83; H, 6.60; N, 11.47. Found: C, 68.78; H, 6.58; N, 11.43.

Example 2
1- (2-phenoxyethyl) -1,6,7,8,9,10-hexahydroazepino [4,5-g] indole

1- (2-phenoxyethyl) -6,7,9,10-tetrahydroazepino [4,5-g] indole-8 (1H) -carboxylic acid (in a flame-dried 50 mL two-necked flask under nitrogen 0.134 g, 0.33 mmol) was dissolved in CH ₂ Cl ₂ (2 mL), β-chlorocatecholborane (0.105 g, 0.66 mmol) was added and the mixture was stirred at room temperature for 3 h. Sodium bicarbonate was added and the mixture was stirred for 30 minutes and then partitioned between CH ₂ Cl ₂ and water. The organic layer was concentrated to dryness in vacuo and the residue was subjected to column chromatography (elution with 5-20% MeOH / CHCl 3 containing 1% methanolic ammonia) to give 0.050 g (50%) of clear Oil was obtained: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42 (d, J = 8 Hz, 1 H), 7.33-7.29 (m, 2 H), 7.11 (d, J = 3 Hz, 1 H ), 7.02-6.95 (m, 2 H), 6.91-6.88 (m, 2 H), 6.51 (d, J = 3 Hz, 1 H), 4.72 (t, J = 6 Hz, 2 H), 4.32 ( t, J = 6 Hz, 2 H), 3.43-3.40 (m, 2 H), 3.13-3.10 (m, 4 H), 3.06-3.03 (m, 2 H); MS (EI) m / z 306 ( HRMS (FAB) Calculated as C ₂₀ H ₂₂ N ₂ O + H 307.1810, found 307.1812. Elemental analysis As C ₂₀ H ₂₂ N ₂ O: Calculated C, 78.40; H, 7.24; N, 9.14.

  The intermediate 1- (2-phenoxyethyl) -6,7,9,10-tetrahydroazepino [4,5-g] indole-8 (1H) -carboxylate tert-butyl was prepared as follows.

2 (a). 1- (2-phenoxyethyl) -6,7,9,10-tetrahydroazepino [4,5-g] indole-8 (1H) -tert-butyl carboxylate Flame-dried 50 mL three-necked flask under nitrogen 1- (2-hydroxyethyl) -6,7,9,10-tetrahydroazepino [4,5-g] indole-8 (1H) -carboxylate tert-butyl, triphenylphosphine (0.177 g, 3 .86 mmol), phenol (0.064 g, 0.675 mmol) and anhydrous THF (3 mL). Di-tert-butyl azodicarboxylate (0.15 g, 0.675 mmol) was added and the mixture was stirred at room temperature for 16 hours. A further aliquot of triphenylphosphine (0.059 g, 0.225 mmol) and di-tert-butyl azodicarboxylate (0.052 g, 0.225 mmol) was added and the mixture was stirred at room temperature for an additional 60 hours. The mixture was concentrated, dissolved in CH ₂ Cl ₂ and subjected directly to column chromatography (elution with 10-30% EtOAc / heptane) to give 0.135 g (74%) of a clear oil. : ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42 (d, J = 8 Hz, 1 H), 7.32-7.26 (m, 2 H), 7.13 (d, J = 3 Hz, 1 H), 7.02- 6.94 (m, 2 H), 6.90-6.87 (m, 2 H), 6. 50 (d, J = 3 Hz, 1 H), 4.73 (t, J = 6 Hz, 2 H), 4.31 (t, J = 6 Hz, 2 H), 3.91-3.70 (m, 2 H), 3.70-3.63 (m, 2 H), 3.46-3.36 (m, 2 H), 3.14-3.05 (m, 2 H), 1.47 (s, 9 H).

Example 3
1- [2- (2-Fluorophenoxy) ethyl] -1,6,7,8,9,10-hexahydroazepino [4,5-g] indole

According to the procedure of Example 2, 1- [2- (2-fluorophenoxy) ethyl] -6,7,9,10-tetrahydroazepino [4,5-g] indole-8 (1H) -carboxylic acid tert- The title compound was prepared from butyl as amber oil (34%): ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42 (d, J = 8 Hz, 1 H), 7.14-7.08 (m, 3 H), 7.04-6.78 (m, 3 H), 6.51 (d, J = 3 Hz, 1 H), 4.74 (t, J = 6 Hz, 2 H), 4.37 (t, J = 7 Hz, 2 H), 3.44 -3.41 (m, 2 H), 3.14-3.05 (m, 6 H).

  The intermediate 1- [2- (2-fluorophenoxy) ethyl] -6,7,9,10-tetrahydroazepino [4,5-g] indole-8 (1H) -carboxylate tert-butyl is as follows: Prepared.

3 (a). 1- [2- (2-Fluorophenoxy) ethyl] -6,7,9,10-tetrahydroazepino [4,5-g] indole-8 (1H) -tert-butyl carboxylate Example 2 (a) The title compound was prepared as a white crystalline solid (74%) using 2-fluorophenol instead of phenol. Melting point 132-134 ° C; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42 (d, J = 8 Hz, 1 H), 7.15-6.86 (m, 6 H), 6.51 (s, 1 H), 4.77 ( t, J = 6 Hz, 2 H), 4.37 (t, J = 6 Hz, 2 H), 3.80-3.70 (m, 2 H), 3.70-3.72 (m, 2 H), 3.46-3.37 (m, 2 H), 3.14-3.05 (m, 2 H), 1.46 (s, 9 H); IR (diffuse reflection) 1690, 1506, 1456, 1423, 1362, 1318, 1282, 1256, 1249, 1201, 1173, 1108, 814, 748, 728cm ^-1 ; MS (EI) m / z 424 (M +); Elemental analysis As C ₂₅ H ₂₉ FN ₂ O ₂ : Calculated value C, 70.73; H, 6.89; N, 6.60. : C, 70.81; H, 6.97; N, 6.51.

Example 4
1- [2- (5,6,7,8-tetrahydro-1-naphthalenyloxy) ethyl] -1,6,7,8,9,10-hexahydroazepino [4,5-g] indole

According to the procedure of Example 2, 1- [2- (5,6,7,8-tetrahydro-1-naphthalenyloxy) ethyl] -6,7,9,10-tetrahydroazepino [4,5-g The title compound was prepared from tert-butyl indole-8 (1H) -carboxylate as a beige foam (54%): ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42 (d, J = 8 Hz, 1 H ), 7.14 (d, J = 3 Hz, 1 H), 7.05 (t, J = 8 Hz, 1 H), 6.95 (d, J = 8 Hz, 1 H), 6.73 (d, J = 8 Hz, 1 H), 6.57 (d, J = 8 Hz, 1 H), 6.50 (d, J = 3 Hz, 1 H), 4.72 (t, J = 6 Hz, 2 H), 4.28 (t, J = 6 Hz, 2 H), 3.52-3.45 (m, 2 H), 3.21-3.00 (m, 6 H), 2.79-2.73 (m, 2 H), 2.64-2.57 (m, 2 H), 1.84-1.73 ( m, 4 H); MS (EI) m / z 360 (M +); HRMS (FAB) Calculated as C ₂₄ H ₂₈ N ₂ O + H 361.2280, found 361.2284.

  Intermediate 1- [2- (5,6,7,8-tetrahydro-1-naphthalenyloxy) ethyl] -6,7,9,10-tetrahydroazepino [4,5-g] indole-8 ( 1H) -tert-butyl carboxylate was prepared as follows.

4 (a). 1- [2- (5,6,7,8-tetrahydro-1-naphthalenyloxy) ethyl] -6,7,9,10-tetrahydroazepino [4,5-g] indole-8 (1H) -Tert-Butyl carboxylate The title compound was prepared as a clear oil (30%) according to the procedure of Example 2 (a) using 5,6,7,8-tetrahydro-1-naphthol instead of phenol: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.37 (d, J = 8 Hz, 1 H), 7.09 (d, J = 3 Hz, 1 H), 6.99 (t, J = 8 Hz, 1 H), 6.89 (d, J = 8 Hz, 1 H), 6.68 (d, J = 8 Hz, 1 H), 6.53 (d, J = 8 Hz, 1 H), 6.44 (d, J = 3 Hz, 1 H ), 4.70 (t, J = 6 Hz, 2 H), 4.23 (t, J = 5 Hz, 2 H), 3.76-3.65 (m, 2 H), 3.65-3.58 (m, 2 H), 3.39- 3.31 (m, 2 H), 3.08-3.00 (m, 2 H), 2.75-2.67 (m, 2 H), 2.59-2.52 (m, 2 H), 1.81-1.79 (m, 4 H), 1.43 ( s, 9 H); IR (liq.) 2973, 2930, 2858, 1692, 1585, 1456, 1421, 1366, 1335, 1326, 1316, 1251, 1170, 1097, 765cm ^-1 ; MS (EI) m / z 460 (M +); HRMS (FAB) Calculated as C ₂₉ H ₃₆ N ₂ O ₃ + H 461.2804, found 461.2814; Elemental analysis As C ₂₉ H ₃₆ N ₂ O ₃ : Calculated C, 75.62; H, 7.88; N , 6.08. Found: C, 75.32; H, 8.17; N, 5.98.

Example 5
1- {2-[(5,5-dimethyl-5,6,7,8-tetrahydro-1-naphthalenyl) oxy] ethyl} -1,6,7,8,9,10-hexahydroazepino [4 , 5-g] indole

According to the procedure of Example 2, 1- {2-[(5,5-dimethyl-5,6,7,8-tetrahydro-1-naphthalenyl) oxy] ethyl} -6,7,9,10-tetrahydroazepino The title compound was prepared as a beige foam (44%) from [4,5-g] indole-8 (1H) -tert-butyl carboxylate: MS (EI) m / z 388 (M +); HRMS (FAB) Calculated as C ₂₅ H ₂₈ N ₂ O ₂ + H 389.2229, measured 389.2200.

  Intermediate 1- {2-[(5,5-dimethyl-5,6,7,8-tetrahydro-1-naphthalenyl) oxy] ethyl} -6,7,9,10-tetrahydroazepino [4,5- g] tert-butyl indole-8 (1H) -carboxylate was prepared as follows.

5 (a). 1- {2-[(5,5-dimethyl-5,6,7,8-tetrahydro-1-naphthalenyl) oxy] ethyl} -6,7,9,10-tetrahydroazepino [4,5-g] Indole-8 (1H) -tert-butyl carboxylate According to the procedure of Example 2 (a), using 5,5-dimethyl-5,6,7,8-tetrahydro-1-naphthol instead of phenol, the title compound Was prepared as a clear oil (74%): MS (EI) m / z 488 (M +).

Example 6
1- [2- (8-Quinolinyloxy) ethyl] -1,6,7,8,9,10-hexahydroazepino [4,5-g] indole

In accordance with the procedure of Example 2, 1- [2- (8-quinolinyloxy) ethyl] -6,7,9,10-tetrahydroazepino [4,5-g] indole-8 (1H) -tert-butyl carboxylate From the title compound as a beige solid (57%). Melting point 129-132 ° C; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.98 (dd, J = 2, 4 Hz, 1 H), 8.14 (dd, J = 2, 8 Hz, 1 H), 7.46-7.36 (m, 4 H), 7.12 (d, J = 3 Hz, 1 H), 6.92 (d, J = 8 Hz, 2 H), 6.47 (d, J = 3 Hz, 1 H), 4.93 (t, J = 7 Hz, 2 H), 4.53 (t, J = 7 Hz, 2 H), 3.42-3.39 (m, 2 H), 3.07-2.98 (m, 6 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 154.1, 149.6, 140.3, 137.1, 136.0, 134.1, 131.2, 129.6, 129.5, 126.6, 124.7, 122.5, 121.7, 120.6, 118.7, 109.4, 102.0, 68.2, 49.0, 48.1, 47.7, 39.6, 31.8; IR (Diffuse reflection) 2928, 2918, 1501, 1464, 1422, 1379, 1361, 1330, 1316, 1261, 1111, 816, 789, 747, 732cm ^-1 ; MS (EI) m / z 357 (M +); HRMS (FAB) Calculated as C ₂₃ H ₂₃ N ₃ O + H 358.1919, measured 358.1927.

  The intermediate tert-butyl 1- [2- (8-quinolinyloxy) ethyl] -6,7,9,10-tetrahydroazepino [4,5-g] indole-8 (1H) -carboxylate is as follows: Prepared.

6 (a). 1- [2- (8-Quinolinyloxy) ethyl] -6,7,9,10-tetrahydroazepino [4,5-g] indole-8 (1H) -tert-butyl carboxylate of Example 2 (a) According to the procedure, 8-hydroxyquinoline was used in place of phenol and the title compound was prepared as a clear oil (93%): ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.00 (s, 1 H), 8.17 (d , J = 8 Hz, 1 H), 7.53-7.37 (m, 4 H), 7.17 (br s, 1 H), 6.95 (dd, J = 1, 7 Hz, 2 H), 6.49 (br s, 1 H), 4.98 (t, J = 6 Hz, 2 H), 4.55 (t, J = 7 Hz, 2 H), 3.77-3.67 (m, 2 H), 3.67-3.61 (m, 2 H), 3.47 -3.38 (m, 2 H), 3.10-3.02 (m, 2 H), 1.41 (s, 9 H); MS (EI) m / z 457 (M +); HRMS (FAB) C ₂₈ H ₃₁ N ₃ O ₃ + H Calculated value 458.2443, Measured value 458.2444.

Example 7
1- {2-[(5,7-dichloro-8-quinolinyl) oxy] ethyl} -1,6,7,8,9,10-hexahydroazepino [4,5-g] indole

According to the procedure of Example 2, 1- {2-[(5,7-dichloro-8-quinolinyl) oxy] ethyl} -6,7,9,10-tetrahydroazepino [4,5-g] indole-8 The title compound was prepared from tert-butyl (1H) -carboxylate as an off-white foam (72%): ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.97 (dd, J = 2, 4 Hz, 1 H ), 8.55 (dd, J = 2,9 Hz, 1 H), 7.66 (s, 1 H), 7.56 (dd, J = 4,9 Hz, 1 H), 7.39 (d, J = 8 Hz , 1 H), 7.22 (d, J = 3 Hz, 1 H), 6.93 (d, J = 8 Hz, 1 H), 6.49 (d, J = 3 Hz, 1 H), 4.90 (t, J = 7 Hz, 2 H), 4.73 (t, J = 7 Hz, 2 H), 3.44-3.40 (m, 2 H), 3.09-3.01 (m, 8 H); MS (EI) m / z 425 (M + ); HRMS (FAB) Calculated as C ₂₃ H ₂₁ Cl ₂ N ₃ O + H 426.1140, found 426.1136; Elemental analysis As C ₂₃ H ₂₁ Cl ₂ N ₃ O: Calculated C, 64.79; H, 4.96; N , 9.86; Cl, 16.63. Found: C, 64.38; H, 5.17; N, 9.55.

  Intermediate 1- {2-[(5,7-dichloro-8-quinolinyl) oxy] ethyl} -6,7,9,10-tetrahydroazepino [4,5-g] indole-8 (1H) -carvone Tert-butyl acid was prepared as follows.

7 (a). 1- {2-[(5,7-dichloro-8-quinolinyl) oxy] ethyl} -6,7,9,10-tetrahydroazepino [4,5-g] indole-8 (1H) -carboxylic acid tert -Butyl The title compound was prepared as a clear oil (88%) according to the procedure of Example 2 (a) using 5,7-dichloro-8-hydroxyquinoline instead of phenol: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.96 (s, 1 H), 8.57-8.50 (m, 1 H), 7.63 (s, 1 H), 7.54 (dd, J = 6, 11 Hz, 1 H), 7.38 (d, J = 11 Hz, 1 H), 7.23 (br, 1 H), 6.96-6.88 (m, 1 H), 6.47 (d, J = 1 Hz, 1 H), 4.90 (t, J = 9 Hz, 2 H ), 4.71 (t, J = 8 Hz, 2 H), 3.73-3.57 (m, 4 H), 3.46-3.37 (m, 2 H), 3.08-3.01 (m, 2 H), 1.45 (s, 9 H); MS (EI) m / z 525 (M +); HRMS (FAB) C ₂₈ H ₂₉ Cl ₂ N ₃ O ₃ + H Calculated 526.1664, Found 526.1666.

Example 8
1- {2-[(5,7-dibromo-8-quinolinyl) oxy] ethyl} -1,6,7,8,9,10-hexahydroazepino [4,5-g] indole

According to the procedure of Example 2, 1- {2-[(5,7-dibromo-8-quinolinyl) oxy] ethyl} -6,7,9,10-tetrahydroazepino [4,5-g] indole-8 The title compound was prepared from tert-butyl (1H) -carboxylate as a clear oil (78%): ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.93 (d, J = 3 Hz, 1 H), 8.51 ( d, J = 9 Hz, 1 H), 8.00 (s, 1 H), 7.57 (dd, J = 4,9 Hz, 1 H), 7.40 (d, J = 8 Hz, 1 H), 7.23 (d , J = 3 Hz, 1 H), 6.93 (d, J = 8 Hz, 1 H), 6.50 (d, J = 3 Hz, 1 H), 4.91 (t, J = 7 Hz, 2 H), 4.73 (t, J = 7 Hz, 2 H), 3.55- 3.47 (m, 2 H), 3.17-3.06 (m, 6 H); HRMS (FAB) Calculated as C ₂₃ H ₂₁ Br ₂ N ₃ O + H 514.0131, Actual value, 514.0136.

  Intermediate 1- {2-[(5,7-dibromo-8-quinolinyl) oxy] ethyl} -6,7,9,10-tetrahydroazepino [4,5-g] indole-8 (1H) -carvone Tert-butyl acid was prepared as follows.

8 (a). 1- {2-[(5,7-Dibromo-8-quinolinyl) oxy] ethyl} -6,7,9,10-tetrahydroazepino [4,5-g] indole-8 (1H) -carboxylic acid tert -Butyl The title compound was prepared as a yellow foam (87%) according to the procedure of Example 2 (a) using 5,7-dibromo-8-hydroxyquinoline instead of phenol: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.92-8.90 (m, 1 H), 8.48 (d, J = 8 Hz, 1 H), 7.95 (s, 1 H), 7.54 (dd, J = 4,9 Hz, 1 H), 7.36 (d, J = 8 Hz, 1 H), 7.21 (br s, 1 H), 6.89 (d, J = 8 Hz, 1 H), 6.44 (d, J = 3 Hz, 1 H), 4.90 (t , J = 7 Hz, 2 H), 4.69 (t, J = 6 Hz, 2 H), 3.72-3.64 (m, 2 H), 3.64-3.57 (m, 2 H), 3.44-3.38 (m, 2 H), 3.07-3.00 (m, 2 H), 1.43 (s, 9 H); IR (diffuse reflection) 1688, 1482, 1451, 1421, 1390, 1385, 1365, 1345, 1318, 1262, 1248, 1209 , 1168, 1106, 809cm ^-1 ; MS (EI) m / z 613 (M +); HRMS (FAB) C ₂₈ H ₂₉ Br ₂ N ₃ O ₃ + H Calculated value 614.0655, Actual value 614.0646.

  Using similar synthetic techniques disclosed herein, the following compounds of formula (I) can also be prepared:

  Example 9: 1- (3-phenoxypropyl) -1,6,7,8,9,10-hexahydroazepino [4,5-g] indole

  Example 10: 8-Methyl-1- (3-phenoxypropyl) -1,6,7,8,9,10-hexahydroazepino [4,5-g] indole

  Example 11: 1- (2- (2,3-Dimethylphenylamino) -2-oxoethyl) -1,6,7,8,9,10-hexahydroazepino [4,5-g] indole

  Example 12: 1- (2- (4-Methylthiazol-3-ylamino) -2-oxoethyl) -1,6,7,8,9,10-hexahydroazepino [4,5-g] indole

The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.

Claims (41)

Formula (I):

[Wherein the bond represented by --- is absent or present;
R ¹ and R ² are independently hydrogen, halo, C _1-8 alkyl, C _3-8 cycloalkyl, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, C _1-8 alkoxy, C _{1 -8} alkoxycarbonyl, C _1-8 alkanoyloxy, R ⁷ C (═O) —, R ⁸ R ⁷ NC (═O) —, R ⁸ R ⁷ N—, aryl, aryl C _1-8 alkylene-, hetero Aryl, heteroaryl C _1-8 alkylene-, Het, or HetC _1-8 alkylene-; or R ¹ and R ^{2 taken} together contain one or more carbon atoms and optionally in the chain one or two oxy (-O-), a thio (-S-), sulfinyl (-SO-), sulfonyl _{(-S (O) 2 -)} , or ^{-NR 10} - including 3, -, 5-, 6-, it is a chain of 7- or 8-membered saturated or partially unsaturated;
R ³ is hydrogen, C _1-8 alkyl, C _3-8 cycloalkyl, aryl, heteroaryl, Het, R ⁷ C (═O) —, R ⁷ OC (═O) —, R ⁷ SO ₂ —, R ^{8 R 7 NC (= O)} -, R 7 C (= S) -, R 7 SC (= O) -, R 8 R 7 NC (= S) -, R 7 SO 2 -, R 8 R 7 NSO _2- , R ⁷ S (═O) —, R ⁸ R ⁷ NS (═O) —, R ^a C _1-8 alkylene-, or R ^a C _1-8 alkylene C (═O) —;
R ^a is aryl, Het, heteroaryl, R ⁷ CO ₂ —, R ⁷ C (═O) —, R ⁷ OC (═O) —, R ⁷ O—, R ⁷ OC _1-8 alkylene O—, R ⁷ S-, R ⁷ C (= S)-, R ⁷ S (= O)-, R ⁷ SC (= O)-, R ⁸ C (= O) N (R ⁷ )-, R ⁸ C (= ^{S) N (R 7) -} , R 8 R 7 N-, R 8 R 7 NC (= O) -, R 8 R 7 NC (= S) -, R 8 R 7 NS (= O) -, R ⁸ R ⁷ NSO ₂ —, R ⁸ S (═O) N (R ⁷ ) —, or R ⁸ SO ₂ N (R ⁷ ) —;
R ⁴ is hydrogen, C _1-8 alkyl, C _3-8 cycloalkyl, aryl, heteroaryl or Het;
R ⁵ and R ⁶ are independently hydrogen, halo, C _1-8 alkyl, C _3-8 cycloalkyl, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, C _1-8 alkoxy, C _{1 -8} alkoxycarbonyl, C _1-8 alkanoyloxy, R ⁷ C (═O) —, R ⁸ R ⁷ NC (═O) —, R ⁸ R ⁷ N—, aryl, aryl C _1-8 alkylene-, hetero Aryl, heteroaryl C _1-8 alkylene-, Het, or HetC _1-8 alkylene-;
R ⁷ and R ⁸ are independently hydrogen, C _1-8 alkyl, C _3-8 cycloalkyl, Het, aryl, heteroaryl, aryl C _1-8 alkylene-, or heteroaryl C _1-8 alkylene- Is;
Where any aryl, heteroaryl or Het of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ is optionally one or more halo, C _{1- 8} alkyl, phenyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, —OR ¹⁰ , —SR ¹⁰ , —SO ₂ R ¹⁰ , —SO ₂ NR ¹⁰ R ¹¹ , —NR ¹⁰ R ¹¹ , —C (═O ^{) NR 10 R 11, -NR 10} C (= O) R 11, -NR 10 C (= O) NR 11 R 12, -CO 2 R 10, -C (= O) R 10, -OC (= O ) R ¹⁰ , optionally substituted with tetrazole, triazole, amidine, guanidine, thioguanidine, or cyanoguanidine;
Here, any ^one of R ¹ , R ² , R ⁵ , R ⁶ , R ⁷ and R ⁸ , C _1-8 alkyl, C _3-8 cycloalkyl, C _1-8 alkoxy, C _1-8 alkanoyl, C _1-8 alkoxycarbonyl or C _1-8 alkanoyloxy is also optionally aryloxy, hydroxy, nitro, halo, cyano, C _1-8 alkoxy, C _1-8 alkanoyl, C _1-8 alkoxycarbonyl, C _{1 -8 ^{alkanoyloxy, R 10 S (O) m}} -, R 11 R 10 NS (O) m -, R 11 R 10 N-, or ^{R 11 R 10 NC (= O} ) - may be substituted by ;
Wherein R ¹⁰ , R ¹¹ and R ¹² are independently hydrogen, C _1-8 alkyl, C _3-8 cycloalkyl, aryl, heteroaryl, aryl C _1-8 alkylene-, or heteroaryl C _{1 -8} alkylene;
Here, any ^one of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ¹⁰ , R ¹¹ and R ¹² , C _1-8 alkyl, C _1-8 Alkylene, C _1-8 alkoxy, C _1-8 alkanoyl, C _1-8 alkoxycarbonyl, C _1-8 alkanoyloxy or C _3-8 cycloalkyl may also be optionally partially unsaturated;
m is 0, 1 or 2]
Or a pharmaceutically acceptable salt thereof. Formula (II):

The compound according to claim 1 or a pharmaceutically acceptable salt thereof. Formula (III):

The compound according to claim 1 or a pharmaceutically acceptable salt thereof. R ¹ and R ² are independently hydrogen, halo, C _1-8 alkyl, C _3-8 cycloalkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, C _1-8 alkoxy, aryl, or aryl 2. A compound according to claim 1 which is _{C1-8alkylene-} . 5. A compound according to claim 4, wherein R < ¹ > and R < ² > are independently hydrogen, aryl or substituted aryl. The compound according to claim 4, wherein one of R ¹ and R ² is phenyl. The compound according to claim 4, wherein one or both of R ¹ and R ² is hydrogen. R ³ is hydrogen, C _1-8 alkyl, C _3-8 cycloalkyl, aryl, heteroaryl, Het, R ⁷ C (═O) —, R ⁷ SO ₂ —, R ⁸ R ⁷ NC (═O) — The compound according to claim 1, which is R ⁷ SC (═O) —, R ^a C _1-8 alkylene-, or R ^a C _1-8 alkylene C (═O) —. R ³ is _{hydrogen, C 1-8} alkyl, aryl, ^{heteroaryl, R 8 R 7 NC (=} O) C 1-8 alkylene -, or ^R 7 _{OC 1-8} alkylene - a is 8. A compound according. The compound of claim 9 wherein R ⁷ is heteroaryl. The compound according to claim 9, wherein R ⁷ is thiazolyl, quinolyl or pyridyl. R ⁷ is at least one fluorine, chlorine, compound of claim 11, wherein the bromine-substituted or _{C 1-8} alkyl. The compound of claim 11, wherein R ⁷ is substituted by at least one methyl. The compound according to claim 9, wherein R ³ is hydrogen or C _1-8 alkyl. The compound of claim 9 wherein R ⁷ is aryl. The compound according to claim 9, wherein R ⁷ is phenyl, naphthyl or tetralyl. R ⁷ is at least one fluorine, chlorine, bromine or _{C 1-8} alkyl compounds of claims 16, wherein substituted with. The compound of claim 16, wherein R ⁷ is substituted by at least one methyl. The compound of claim 1 wherein R ⁴ is hydrogen, C _1-8 alkyl, aryl or substituted aryl. The compound of claim 19 wherein R ⁴ is hydrogen or methyl. R ⁵ and R ⁶ are independently hydrogen, halo, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, C _1-8 alkoxy, C _1-8 alkoxycarbonyl, C _1-8 alkanoyloxy, aryl Or a substituted aryl. R ⁵ and R ⁶ are independently hydrogen, aryl or compound of claim 21 wherein the substituted aryl. The compound according to claim 21, wherein R ⁵ and R ⁶ are independently hydrogen or phenyl. The compound according to claim 21, wherein R ⁵ and R ⁶ are each hydrogen. A R ^{1, R 2} and ^{R 3} are each hydrogen, A compound according to claim 5, wherein ^{R 4} is methyl. 8-methyl-1,6,7,8,9,10-hexahydroazepino [4,5-g] indole;
1- (2-phenoxyethyl) -1,6,7,8,9,10-hexahydroazepino [4,5-g] indole;
1- [2- (2-fluorophenoxy) ethyl] -1,6,7,8,9,10-hexahydroazepino [4,5-g] indole;
1- [2- (5,6,7,8-tetrahydro-1-naphthalenyloxy) ethyl] -1,6,7,8,9,10-hexahydroazepino [4,5-g] indole ;
1- {2-[(5,5-dimethyl-5,6,7,8-tetrahydro-1-naphthalenyl) oxy] ethyl} -1,6,7,8,9,10-hexahydroazepino [4 , 5-g] indole;
1- [2- (8-quinolinyloxy) ethyl] -1,6,7,8,9,10-hexahydroazepino [4,5-g] indole;
1- {2-[(5,7-dichloro-8-quinolinyl) oxy] ethyl} -1,6,7,8,9,10-hexahydroazepino [4,5-g] indole;
1- {2-[(5,7-dibromo-8-quinolinyl) oxy] ethyl} -1,6,7,8,9,10-hexahydroazepino [4,5-g] indole;
1- (3-phenoxypropyl) -1,6,7,8,9,10-hexahydroazepino [4,5-g] indole;
8-methyl-1- (3-phenoxypropyl) -1,6,7,8,9,10-hexahydroazepino [4,5-g] indole;
1- (2- (2,3-dimethylphenylamino) -2-oxoethyl) -1,6,7,8,9,10-hexahydroazepino [4,5-g] indole;
1- (2- (4-methylthiaza-3-ylamino) -2-oxoethyl) -1,6,7,8,9,10-hexahydroazepino [4,5-g] indole;
Or a pharmaceutically acceptable salt thereof.   A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.   2. A compound according to claim 1 for use in medical diagnosis or therapy.   29. The compound of claim 28, wherein the treatment is treatment of a central nervous system disease or disorder.   29. The compound of claim 28, wherein the treatment is treatment of anxiety, obesity, depression or stress-related disease.   Use of a compound according to claim 1 for the manufacture of a medicament for treating or preventing a disease or disorder of the central nervous system.   32. The use according to claim 31, wherein the disease or disorder of the central nervous system is anxiety, obesity, depression or stress-related disease.   A 5-HT receptor is implicated in a mammal in need thereof, wherein a therapeutically effective amount of the compound of claim 1 is administered to the mammal, and modulation of 5-HT function is desired A method of treating a disease or disorder.   34. The method of claim 33, wherein the disease is anxiety, obesity, depression or stress-related disease.   A method of treating or preventing a central nervous system disease or disorder in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of the compound of claim 1. Formula IV:

[Wherein R ¹ and R ² are independently hydrogen, halo, C _1-8 alkyl, C _3-8 cycloalkyl, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, C _1-8. Alkoxy, C _1-8 alkoxycarbonyl, C _1-8 alkanoyloxy, R ⁷ C (═O) —, R ⁸ R ⁷ NC (═O) —, R ⁸ R ⁷ N—, aryl, aryl C _1-8 Alkylene-, heteroaryl, heteroarylC _1-8 alkylene-, Het or HetC _1-8 alkylene-; or R ¹ and R ^{2 taken} together contain one or more carbon atoms and optionally a chain one or two oxy in (-O-), thio (-S-), sulfinyl (-SO-), sulfonyl _{(S (O) 2 -)} , or ^{-NR 10} - include a 3-, 4-, 5-, 6-, be a chain of 7- or 8-membered saturated or partially unsaturated;
R ³ is hydrogen, C _1-8 alkyl, C _3-8 cycloalkyl, aryl, heteroaryl, Het, R ⁷ C (═O) —, R ⁷ OC (═O) —, R ⁷ SO ₂ —, R ^{8 R 7 NC (= O)} -, R 7 C (= S) -, R 7 SC (= O) -, R 8 R 7 NC (= S) -, R 7 SO 2 -, R 8 R 7 NSO _2- , R ⁷ S (═O) —, R ⁸ R ⁷ NS (═O) —, R ^a C _1-8 alkylene- or R ^a C _1-8 alkylene C (═O) —; and PG Is COOMe or Boc]
Compound.   37. The compound of claim 36, wherein PG is COOMe.   37. The compound of claim 36, wherein PG is Boc. R ³ is 36. A compound according is hydrogen or _{C 1-8} alkyl. R ¹ and R ² are independently hydrogen, aryl or compound of claim 36 wherein the substituted aryl. R ^1, compound of claim 36 wherein ^{R 2} and ^{R 3} are hydrogen.